Prostate cancer is a complex disease characterized by recurrent gene deletions and amplifications. Human genetic data demonstrate correlation between dual loss of CHD1 and MAP3K7 with lethal prostate cancer. We recently showed in both published and unpublished data that MAP3K7 and CHD1 loss leads to aggressive castrate-resistant prostate cancer. We did this with two independent model systems providing strong support for the overall conclusions of the studies that provide a functional link between these two novel tumor suppressors and prostate cancer aggressiveness. Because MAP3K7 and CHD1 are both tumor suppressors, and by definition lost or inactivated in prostate cancer, neither are directly targetable with therapeutic strategies. We hypothesize that cells with loss of MAP3K7 and CHD1 have dependence on novel survival pathways and we propose to exploit these pathways to kill tumors that have lost MAP3K7 and/or CHD1. We will use two complementary approaches to identify therapeutic vulnerabilities. In Aim 1 we will screen human prostate cells with knockdown of CHD1 and/or MAP3K7 for the ability of common prostate cancer drugs to inhibit growth and tumorigenesis in vitro and in vivo. In aim 2 we will use a genome-wide shRNA screen to identify synthetic lethal targets in cells with loss of MAP3K7 and/or CHD1. This is a high-risk, high-gain project appropriate for an R21 type funding mechanism. Each aim is independent and each needs to be done. Together the two aims will define potential therapeutic approaches to an extremely aggressive variant of prostate cancer.